MICROSTRUCTURAL CHANGES IN FRONTAL WHITE MATTER ASSOCIATED WITH CANNABIS USE IN EARLY PHASE PSYCHOSIS: A

DIFFUSION TENSOR IMAGING (DTI) STUDY

by

Jacob I. Cookey

Submitted in partial fulfilment of the requirements for the degree of Master of Science

at

Dalhousie University Halifax, Nova Scotia

August 2014

Copyright by Jacob I. Cookey, 2014

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In dedication to the patients and family members who are affected by schizophrenia spectrum and other psychotic disorders

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Table Of Contents List Of Tables ............................................................................................................. vi List Of Figures ........................................................................................................... vii Abstract ..................................................................................................................... viii List Of Abbreviations Used ........................................................................................ ix Acknowledgements .................................................................................................... xii Chapter 1 Introduction .............................................................................................. 1 1.1 Schizophrenia and Other Psychotic Disorders ..................................... 1 1.1.1 Epidemiology, Clinical Manifestations, Diagnosis ................. 1 1.1.2 Early Phase Psychosis ............................................................. 3 1.1.3 Etiology and Pathophysiology ................................................. 4 1.2 Cannabis Use and Early Phase Psychosis ............................................ 8 1.2.1 Epidemiology of Cannabis Use ............................................... 8 1.2.2 Biological Effects of Cannabis ................................................ 8 1.2.3 Role of Cannabis Use in Early Phase Psychosis ..................... 9 1.3 White Matter Disturbances in Early Phase Psychosis ....................... 12 1.3.1 What is White Matter? ........................................................... 12 1.3.1.1 White Matter Tracts/Families ................................... 12 1.3.2 Rationale for Studying White Matter in Psychosis ............... 13 1.4 Diffusion Tensor Imaging (DTI) in Early Phase Psychosis ............... 14 1.4.1 Basic Principles of MRI ........................................................ 14 1.4.2 Basic Principles of DTI ......................................................... 15 1.4.3 DTI measures ......................................................................... 17

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1.5 Application of DTI to Early Phase Psychosis and Cannabis Use: Review of the Literature ............................................................ 18 1.5.1 DTI in Early Phase Psychosis: Illness Effect ........................ 18 1.5.2 DTI in Cannabis Use: Drug Effect ........................................ 21 1.5.3 DTI in Early Phase Psychosis with Cannabis Use: Combined Illness and Drug Effects ....................................... 22 1.5.4 Conclusion ............................................................................. 23 1.6 Study Objectives ................................................................................ 24 1.6.1 Purpose .................................................................................. 24 1.6.2 Hypotheses ............................................................................ 25 Chapter 2 Materials and Methods ........................................................................... 26 2.1 Power Analysis .................................................................................. 26 2.2. Participants ........................................................................................ 26 2.3 Clinical Measures ............................................................................... 28 2.4 DTI Acquisition and Data Analysis ................................................... 30 2.5 DTI Statistical Analysis ..................................................................... 31 Chapter 3 Results ...................................................................................................... 34 3.1 Clinical and Demographic Variables ................................................. 34 3.2 Effect of Early Phase Psychosis (Hypothesis 1) ................................ 35 3.3 Associations: Cannabis Use and DTI Measures (Hypothesis 2&3) .. 36 3.3.1 Correlation Between Lifetime Cannabis Use and Mean FA .......................................................................................... 36 3.3.2 Correlation Between Age of Onset of Cannabis Use and Mean FA ................................................................................ 37 3.4 Exploratory Analyses ......................................................................... 37

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3.4.1 Illness Effects ........................................................................ 37 3.4.2 Cognitive Measures ............................................................... 38 3.4.3 Symptom/Function Measures ................................................ 38 3.4.4 Substance Use Measures ....................................................... 39 3.5 Results Summary ............................................................................... 40 Chapter 4 Discussion ................................................................................................ 42 4.1 Primary Outcome Measures ............................................................... 42 4.1.1 Effect of Early Phase Psychosis (Hypothesis 1) .................... 42

4.1.2 Effect of Cannabis Use (Hypothesis 2 & 3) .......................... 43 4.2 Exploratory Analyses ......................................................................... 48 4.2.1 Illness Effects ........................................................................ 48 4.2.2 Cognitive Measures ............................................................... 49 4.2.3 Symptom/Function Measures ................................................ 50 4.2.4 Substance Use Measures ....................................................... 53 4.3 Summary ............................................................................................ 54 4.4 Conclusion ......................................................................................... 55 4.5 Study Limitations ............................................................................... 56 4.6 Future Directions ............................................................................... 57 4.7 Implications ........................................................................................ 58

References .................................................................................................................. 75 Appendix A Copyright permission for figures 1 & 2 ............................................. 88 Appendix B Copyright permission for publication (Cookey et al, 2014) ............. 89

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List of Tables

Table 1 Outline of literature search: count of studies as a function of each population .................................................................................. 59 Table 2 Diffusion Tensor Imaging studies retained in literature review ......... 61 Table 3 Affected group of fiber tracts in early phase schizophrenia ............... 62 Table 4 Demographics and clinical characteristics ......................................... 63 Table 5 MRI Safety Checklist ......................................................................... 64 Table 6 Outline of neuroimaging acquisitions ................................................ 65 Table 7 DTI measures ..................................................................................... 66 Table 8 Non-parametric correlation matrix VOI .......................................... 67 Table 9 Parametric correlation matrix VOI .................................................. 68 Table 10 Non-parametric correlation matrix full-brain .................................. 69 Table 11 Parametric correlation matrix full-brain .......................................... 70

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List of Figures

Figure 1 Illustration of water molecule (represented by red dot) randomly moving within an axon. Notice that more movement is permitted along the length of the axon rather than orthogonal to it ................................................................. 71 Figure 2 Illustration of the football-shaped diffusion tensor ............................ 72 Figure 3 Voxel Of Interest left Superior Longitudinal Fasciculus ................ 73 Figure 4 DTI FA maps of primary diffusion vector (V1) color coded for 3D diffusion directionality ............................................................ 74

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Abstract

Introduction: This project aimed to examine the impact of cannabis use on the

brain white matter (WM) tissue abnormalities associated with psychosis, in

individuals at the early phase of psychosis (< 5 years from diagnosis). Using diffusion

tensor imaging (DTI), it was predicted that there would be evidence of WM

disruption in patients with psychosis compared to healthy controls, and more so in

patients with earlier and heavier lifetime cannabis use. Methods: The primary

outcome measure was fractional anisotropy (FA) which reflects WM integrity. There

were two groups of subjects: 1) Patients with early phase psychosis a